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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by DigitalCommons@Florida International University Florida International University FIU Digital Commons Robert Stempel College of Public Health & Social Departments of Biostatistics Work 10-23-2015 Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer Deodutta Roy Department of Environmental and Occupational Health, Florida International University, [email protected] Marisa L. Morgan Department of Environmental and Occupational Health, Florida International University, [email protected] Changwon Yoo Department of Biostatistics, Florida International University, [email protected] Alok Deoraj Department of Environmental and Occupational Health, Florida International University, [email protected] Sandhya Roy BMSNF Inc. See next page for additional authors Follow this and additional works at: http://digitalcommons.fiu.edu/biostatistics_fac Part of the Biostatistics Commons, and the Medicine and Health Sciences Commons Recommended Citation Roy, Deodutta; Morgan, Marisa L.; Yoo, Changwon; Deoraj, Alok; Roy, Sandhya; Yadav, Vijay Kumar; Garoub, Mohannad; Assaggaf, Hamza; and Doke, Mayur, "Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer" (2015). Departments of Biostatistics. Paper 3. http://digitalcommons.fiu.edu/biostatistics_fac/3 This work is brought to you for free and open access by the Robert Stempel College of Public Health & Social Work at FIU Digital Commons. It has been accepted for inclusion in Departments of Biostatistics by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. Authors Deodutta Roy, Marisa L. Morgan, Changwon Yoo, Alok Deoraj, Sandhya Roy, Vijay Kumar Yadav, Mohannad Garoub, Hamza Assaggaf, and Mayur Doke This article is available at FIU Digital Commons: http://digitalcommons.fiu.edu/biostatistics_fac/3 Int. J. Mol. Sci. 2015, 16, 25285-25322; doi:10.3390/ijms161025285 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Article Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer Deodutta Roy 1,*, Marisa Morgan 1, Changwon Yoo 2, Alok Deoraj 1, Sandhya Roy 3, Vijay Kumar Yadav 4, Mohannad Garoub 1, Hamza Assaggaf 1 and Mayur Doke 1 1 Department of Environmental & Occupational Health, Florida International University, Miami, FL 33199, USA; E-Mails: [email protected] (M.M.); [email protected] (A.D.); [email protected] (M.G.); [email protected] (H.A.); [email protected] (M.D.) 2 Department of Biostatistics, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA; E-Mail: [email protected] 3 BMSNF Inc., Aventura, FL 33180, USA; E-Mail: [email protected] 4 Department of Physics, GKPD College, Karpoorigram, Samastipur 848129, India; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-305-348-1694; Fax: +1-305-348-4901. Academic Editor: Paul B. Tchounwou Received: 18 August 2015 / Accepted: 12 October 2015 / Published: 23 October 2015 Abstract: We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in Int. J. Mol. Sci. 2015, 16 25286 endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors. Keywords: bioinformatics; breast cancer; bisphenol A; endocrine disruptors; endometriosis; genomics; PCBs; phthalates 1. Introduction Breast cancer and endometriosis are multifactorial complex chronic diseases with both genetic and environmental contributors. Many environmental and molecular risk factors common to breast cancer and endometriosis have received insufficient attention in molecular epidemiologic investigations because these studies have reported inconsistent results of an association with these contributors. Both breast cancer and endometriosis have in common one of the etiological factors, i.e., estrogen [1]. Unopposed estrogen stimulates the growth of endometrial cells in the uterus as well as proliferation of breast cells. Tamoxifen, a hormonal therapy for breast cancer, stimulates the growth of endometrial cells and can cause endometriosis [2]. Altered endogenous estrogen is linked with an increased risk of endometriosis and breast cancer among postmenopausal women [3–5]. Recently, a new report by the United Nations Environment Programme (UNEP) and World Health Organization (WHO) entitled “State of the Science: Endocrine Disrupting Chemicals-2012” highlighted that approximately 800 chemicals are suspected to act as endocrine disruptors (EDs) or mimic natural hormones or disrupt hormone regulation [6,7]. Some of these EDs mimic natural or synthetic estrogen. This recent UNO report has renewed the concern by highlighting that there may be some associations between exposure to estrogen-mimicking EDs and an increased risk of breast cancer in women [6,7]. The estrogen mimicking EDs include a variety of chemicals such as pesticides, fungicides, industrial compounds, by-products of industrial processes, and chemicals used in the manufacturing of plastics. Indeed the estrogen-mimicking EDs that are persistent in the environment, highly lipophilic, and they readily bio-accumulate and magnify within the food chain [4–7]. Many of these chemicals are used in a variety of consumer products; therefore exposure to endocrine disrupting chemicals (EDCs) among the general population is widespread. Human exposure to EDCs may result from inhalation through the air, absorption through the skin, and most commonly through the ingestion of contaminated food and water [8,9]. EDCs may produce a wide range of adverse effects because of the complexity of the endocrine system with its multiple signaling pathways, feedback mechanisms and cross-talks. Although a number of experimental animal studies have shown that many chemicals have potential endocrine disrupting activities, the data, however, on their endocrine disrupting effects in humans is limited. The role of EDC’s in the etiology of some of the human cancers and reproductive health hazards has been implicated, although the linkage between these two processes is highly controversial [8]. In addition to their endocrine disrupting effects, some environmental estrogen-like chemicals produce multiple genetic and/or non-genetic hits, which may contribute to the induction of genomic instability in stem cells [4]. In the last decade, exposure to multiple EDCs such as polychlorinated biphenyls (PCBs), phthalates, and Int. J. Mol. Sci. 2015, 16 25287 bisphenol A (BPA) have been detected in >90% of blood and urine samples collected [8,10–12]. PCBs have been shown to interfere with reproductive function and development in animals and humans by either increasing or blocking estrogen activity [4–7]. Adverse reproductive health effects have been established in a number of animal studies that linked PCB exposures to decreased sperm fertilizing ability in mice [13], changes in the uterine myometrium and gland formation in mice [14], and a significant dose-dependent relationship in the prevalence and severity of endometriosis in rhesus monkeys [15]. Among phthalates, di-(2-ethylhexyl) phthalate (DEHP), di-butyl phthalate (DBP) and butylbenzylphthalate (BBP) have been studied for their endocrine disrupting effects. Phthalates have been shown to produce anti-androgenic effects by suppressing testosterone and estrogen production. Exposure to high levels of phthalate have been reported to result in reproductive abnormalities in female rodents that included increased uterine and ovarian weights and malformations, delayed onset of puberty; and modified morphology of the mammary gland [16]. The majority of human exposure to BPA is via ingestion of contaminated food products [4,9]. We have shown that BPA is oxidized to bisphenol-o-quinone by cytochrome P450 activation system. Administration of a single dose or multiple doses of 200 mg/kg of BPA to CD1 male rats produces in vivo DNA adducts
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